Clark Lauren K, Green Todd J, Petit Chad M
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama 35294, USA.
Department of Microbiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama 35294, USA.
bioRxiv. 2020 Nov 3:2020.11.03.366757. doi: 10.1101/2020.11.03.366757.
The periodic emergence of novel coronaviruses (CoVs) represents an ongoing public health concern with significant health and financial burden worldwide. The most recent occurrence originated in the city of Wuhan, China where a novel coronavirus (SARS-CoV-2) emerged causing severe respiratory illness and pneumonia. The continual emergence of novel coronaviruses underscores the importance of developing effective vaccines as well as novel therapeutic options that target either viral functions or host factors recruited to support coronavirus replication. The CoV nonstructural protein 1 (nsp1) has been shown to promote cellular mRNA degradation, block host cell translation, and inhibit the innate immune response to virus infection. Interestingly, deletion of the nsp1-coding region in infectious clones prevented the virus from productively infecting cultured cells. Because of nsp1's importance in the CoV lifecycle, it has been highlighted as a viable target for both antiviral therapy and vaccine development. However, the fundamental molecular and structural mechanisms that underlie nsp1 function remain poorly understood, despite its critical role in the viral lifecycle. Here we report the high-resolution crystal structure of the amino, globular portion of SARS-CoV-2 nsp1 (residues 10 - 127) at 1.77Å resolution. A comparison of our structure with the SARS-CoV-1 nsp1 structure reveals how mutations alter the conformation of flexible loops, inducing the formation of novel secondary structural elements and new surface features. Paired with the recently published structure of the carboxyl end of nsp1 (residues 148 - 180), our results provide the groundwork for future studies focusing on SARS-CoV-2 nsp1 structure and function during the viral lifecycle.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic. One protein known to play a critical role in the coronavirus lifecycle is nonstructural protein1 (nsp1). As such, it has been highlighted in numerous studies as a target for both the development of antivirals and for the design of live-attenuated vaccines. Here we report the high-resolution crystal structure of nsp1 derived from SARS-CoV-2 at 1.77Å resolution. This structure will facilitate future studies focusing on understanding the relationship between structure and function for nsp1. In turn, understanding these structure-function relationships will allow nsp1 to be fully exploited as a target for both antiviral development and vaccine design.
新型冠状病毒（CoV）的周期性出现是一个持续存在的公共卫生问题，在全球范围内造成了重大的健康和经济负担。最近一次疫情起源于中国武汉市，一种新型冠状病毒（SARS-CoV-2）出现，导致严重的呼吸道疾病和肺炎。新型冠状病毒的不断出现凸显了开发有效疫苗以及针对病毒功能或支持冠状病毒复制的宿主因子的新型治疗选择的重要性。冠状病毒非结构蛋白1（nsp1）已被证明可促进细胞mRNA降解、阻断宿主细胞翻译并抑制对病毒感染的先天免疫反应。有趣的是，感染性克隆中nsp1编码区的缺失阻止了病毒有效感染培养细胞。由于nsp1在冠状病毒生命周期中的重要性，它已被视为抗病毒治疗和疫苗开发的可行靶点。然而，尽管nsp1在病毒生命周期中起着关键作用，但其功能背后的基本分子和结构机制仍知之甚少。在此，我们报告了SARS-CoV-2 nsp1氨基端球状部分（第10 - 127位氨基酸残基）的高分辨率晶体结构，分辨率为1.77Å。将我们的结构与SARS-CoV-1 nsp1结构进行比较，揭示了突变如何改变柔性环的构象，诱导形成新的二级结构元件和新的表面特征。结合最近发表的nsp1羧基端（第148 - 180位氨基酸残基）结构，我们的结果为未来聚焦于SARS-CoV- nsp1在病毒生命周期中的结构和功能的研究奠定了基础。
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是COVID-19大流行的病原体。已知一种在冠状病毒生命周期中起关键作用的蛋白质是非结构蛋白1（nsp1）。因此，在众多研究中它被视为抗病毒药物开发和减毒活疫苗设计的靶点。在此，我们报告了源自SARS-CoV-2的nsp1的高分辨率晶体结构，分辨率为1.77Å。该结构将有助于未来聚焦于理解nsp1结构与功能关系的研究。反过来，理解这些结构-功能关系将使nsp1能够被充分用作抗病毒药物开发和疫苗设计的靶点。
